inphase opposed phase imaging of bone marrow...
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“INPHASE OPPOSED PHASE IMAGING OF BONE
MARROW DIFFERENTIATING NEOPLASTIC
LESIONS FROM NON NEOPLASTIC LESIONS”
Dissertation submitted for
M.D. DEGREE EXAMINATION
BRANCH VIII – RADIODIAGNOSIS
MADRAS MEDICAL COLLEGE
AND
GOVERNMENT GENERAL HOSPITAL
CHENNAI – 600 003
THE TAMIL NADU DR.M.G.R MEDICAL UNIVERSITY
CHENNAI – 600 032
APRIL 2011
“Learn to heal”
Prof. J. MOHANASUNDARAM, M.D.,D.N.B ;Ph.D.,DEAN,
MADRAS MEDICAL COLLEGE &GOVERNMENT GENERAL HOSPITAL
CHENNAI – 600 003.
CERTIFICATE
This is to certify that Dr. N.SUNDARESWARAN has been a post
graduate student during the period April 2008 to April 2011 at Barnard In-
stitute of Radiology, Madras Medical College, Government General Hos-
pital, Chennai.
This Dissertation titled “INPHASE OPPOSED PHASE IMAGING OF
BONE MARROW DIFFERENTIATING NEOPLASTIC LESIONS FROM
NON NEO PLASTIC LESIONS” is a bonafide work done by him during the
study period and is being submitted to the Tamilnadu Dr. M.G.R. Medical
University in partial ful fillment of the M.D. Branch VIII Radiodiagnosis
Examination
PROF.K.VANITHA M.D.,D.M.R.D., D.R.M.,DIRECTOR,BARNARD INSTITUTE OF RADIOLOGYMADRAS MEDICAL COLLEGE &GOVERNMENT GENERAL HOSPITALCHENNAI - 600 003.
PROF.N.KAILASANATHAN M.D.,D.M.R.D.,HEAD OF THE DEPARTMENT,BARNARD INSTITUTE OF RADIOLOGYMADRAS MEDICAL COLLEGE &GOVERNMENT GENERAL HOSPITALCHENNAI - 600 003.
DECLARATION
I Dr.N.SUNDARESWARAN, solemnly declare that this
dissertation entitled, “INPHASE OPPOSED IMAGING OF BONE
MARROW DIFFERENTIATING NEOPLASTIC LESIONS
FROM NON NEOPLASTIC LESIONS” is a bonafide work done by
me at the Barnard Institute of Radiology, Madras Medical College and
Government General Hospital during the period 2008 – 2010 under the
guidance and supervision of the Director, Barnard Institute of Radiology
of Madras Medical College and Government General Hospital, Profes-
sor K. Vanitha, M.D., D.M.R.D., D.R.M., This dissertation is submit-
ted to The Tamil Nadu Dr. M.G.R Medical University, towards partial
fulfillment of requirement for the award of M.D. Degree
Radiodiagnosis.
Place : Chennai
Date: 30.11.10 Dr. N.SUNDARESWARAN
ACKNOWLEDGEMENTS
I would like to thank Prof. J. MOHANASUNDARAM, M.D., D.N.B.,
Ph.D., Dean, Madras Medical College, Government General Hospital, Chen-
nai, for giving me permission to conduct the study in this institution.
With extreme gratefulness, I express my indebtedness to
Prof. K. VANITHA, M.D., D.M.R.D., D.R.M., Director, Barnard Institute of Ra-
diology, for having encouraged me to take up this study. But for her guiding
spirit, perseverance and wisdom, this study would not have been possible.
I express my sincere thanks and gratitude to
Prof. T.S. SWAMINATHAN, M.D., D.M.R.D., F.I.C.R.,
Prof. N. KULASEKERAN, M.D., D.M.R.D., Prof. M. PRABAKARAN, M.D.,
D.M.R.D., Former Directors, Barnard Institute of Radiology for their immense
kindness, constant support and consistent encouragement in conducting this
study.
I am deeply indebted to my H.O.D, Prof. N. KAILASANATHAN,
M.D., D.M.R.D., whose help, stimulating suggestions and encouragement helped
me in the research and writing of this thesis.
I wish to thank Prof. K.MALATHY, M.D.,D.M.R.D.,
Prof. A.P. ANNADURAI, M.D., D.M.R.D., and Prof. K. THAYALAN for
their support, valuable criticisms and encouragement.
I am greatly indebted to my assistant professors
Dr.S.SUNDARESWARAN, D.M.R.D., Dr.S.KALPANA, M.D., D.M.R.D., D.N.B.,
Dr. S. BABU PETER, M.D.R.D., D.N.B., Dr. D. RAMESH, M.D.R.D.,
Dr.C.AMARNATH, M.D.,D.N.B.,F.R.C.R., Dr.J.DEVIMEENAL,M.D., D.M.R.D.,
D.N.B., Dr. MANIMEKALA, M.D.R.D., and fellow postgraduates for their un-
tiring help.
Last but not the least; I thank all my patients for their cooperation,
without whom this study would not have been possible
CONTENTS
Page
1. INTRODUCTION 1
2. AIM OF THE STUDY 4
3. REVIEW OF LITERATURE 5
4. MATERIAL AND METHODS 27
5. OBSERVATION AND RESULTS 33
6. DISCUSSION 42
7. CONCLUSION 48
8. BIBLIOGRAPHY
9 ANNEXURES
PROFORMA
CONSENT FORM
ABBERVIATIONS
MASTER CHART
1
INTRODUCTION
MAGNETIC RESONANCE (MR) imaging has become preferred
over other imaging modalities in evaluating disease in the bone marrow.
The bone marrow represents 5% of body weight and consists of
hematopoietic components (40% fat, and 40% water, and 20%protein)
and lipomatous components (80% fat, 15% water, 5% protein) with a
variable trabecular bone lattice. Bone marrow is a richly vascularised,
dynamic and highly responsive system that is prominently targeted in
many physiologic and pathologic processes. It is a non invasive
technique complements bone marrow aspirations and biopsies by
sampling a large volume of bone marrow and by providing information
that aids the diagnosis, staging, and follow-up of hematologic
malignancies.
Conventionally, bone marrow is examined by means of bone
marrow aspiration biopsy or trephinement of the posterior iliac crest.
Both techniques provide a localized view of the state of the marrow and
may be subject to sampling errors when used in disorders known to
affect the marrow focally. An objective and non invasive method of
assessing and characterizing bone marrow would be a useful clinical
adjunct to bone marrow aspiration and trephinement.
2
Examination of the bone marrow has traditionally been provided
by biopsy or aspiration approaches or by relatively insensitive or
non-specific techniques such as scintigraphy, radiography or computed
tomography. MR, with its multifaceted imaging and quantitative
capabilities, has found wide application in the assessment of the bone
marrow, both on a research and clinical basis.
Each of the various MR pulse sequences, ranging from
spin-echo(SE), and short TI inversion recovery (STIR) to more
advanced chemical shift techniques (opposed phase) offers unique
opportunities to detect, assess and quantify the many processes affecting
the bone marrow. These processes include age-related marrow
conversion and reconversion, hematologic disorders, diffuse and focal
neoplastic processes, storage and marrow packing disorders, ischemic
and hyperaemic conditions, traumatic and infectious processes, toxic
exposures, and metabolic bone disorders such as osteoporosis. The
age-related patterns of hemateopoietic tissue regression from the
appendicular skeleton and the progressive conversion of marrow in the
axial skeleton are well documented.
3
Variable reconversion patterns, particularly well defined with
opposed phase sequences have been observed. Non-neoplastic
hematologic conditions, ranging from hemolytic anemia with myeloid
hyperplasia and reconversion to aplastic anemia with myeloid depletion,
have been widely investigated with various MR techniques. Marrow-
based neoplastic processes, both diffuse and focal, have also been
extensively studied with MR.
4
AIM & OBJECTIVES
Neoplastic and non neoplastic lesions in the bone marrow may
have similar signal intensity on conventional MR imaging sequences.
(i) Purpose of this study is whether inphase opposed phase imaging
can helps to differentiate neoplastic and non neoplastic lesions
of bone marrow
(ii) To assess sensitivity and specificity of inphase opposed phase
imaging in Differentiating neoplastic and non neoplastic lesions
of bone marrow
5
REVIEW OF LITERATURE
MRI of Bone Marrow
Normal Anatomy
The normal bone marrow has three primary components: osseous
matrix, red marrow, and yellow marrow. The osseous components of the
marrow are the trabeculae of cancellous bone, which provide the
supporting framework for the red and yellow marrow elements. The red
or cellular marrow is hematopoietically active,producing RBCs, WBCs,
and platelet precursors. Hematopoietically inactive yellow marrow is
composed of fat cells. These two types of marrow differ in their
chemical composition. Recognition of these differences is important to
understanding the MRI appearance of marrow.
In infants and young children, red marrow consists of approxi-
mately 40% water, 40% fat, and 20% protein .As the individual ages,
the fatty elements of hematopoietic marrow increase, and by age 70
years, red marrow is composed of approximately 60% fat, 30% water,
and 10% protein. Yellow marrow contains approximately 80% fat,
15% water, and 5% protein
6
BONE MARROW PHYSIOLOGY
The bone marrow is the 5th largest organ of the human body.
Its chief function is hematopoietic, providing the optimal supply of
circulating platelets, white and red blood cells to meet the body´s
requirements for coagulation, immunity, and oxygenation.
The histology of normal bone marrow consists of a number of
components including: (1) an osseous component; (2) a cellular
component; (3) a supporting system. The osseous component consists of
cancellous bone composed of primary and secondary trabeculae. The
cellular component includes hematopoietic, fat, and reticulum cells. The
bone marrow supporting system consists of vascular, neural, and
lymphatic celements.
Hematopoietically active bone marrow is referred to as
hematopoietic marrow or red marrow. Red marrow contains
approximately water,40% fat, and 20% protein. Hematopoietically
inactive marrow is referred to as yellow marrow or fatty marrow. It
contains approximately 15% water, 80% fat, and 5% protein. These
differences in chemical composition account for the appearance of red
and yellow marrow on various MRI pulse sequences. There is also a
7
structural difference between red and yellow marrow. In particular, the
vascular network of red marrow can be characterized as being rich,
while that of yellow marrow is more sparse.
At birth, red marrow is present throughout the entire skeleton.
Epiphyses and apophyses are cartilaginous at birth; however, they later
contain yellow marrow throughout life. Epiphyseal red marrow can be a
normal variant in adults, however, in the humeral head and femoral
head. Normal physiological conversion of red-to yellow marrow occurs
in a predictable and orderly fashion with completion by the age of 25
years when the adult pattern is reached.
Conversion occurs first in the hands and feet. There is then a
“distal to proximal“ trend of conversion within the bones of the
extremities. Conversion also occurs at different rates within the same
bone. Within long bones, marrow converts first in the diaphysis, then in
the distal metaphysis, and finally in the proximal metaphysis. By age 25
years, the adult distribution of bone marrow is attained which is
characterized by red marrow persisting in the axial skeleton, proximal
humerus, and proximal femur. With advancing age there is further
replacement of red marrow by yellow marrow, with older individuals
commonly having a spine and pelvis dominated by yellow marrow.
8
Residual islands of hematopoietic marrow can persist in the long bones.
The most common sites are the proximal and distal femur, and proximal
humerus. This pattern should not be mistaken for pathology. Another
common normal variation in distribution of marrow is the presence of
focal fatty marrow within the spine. The distal appendicular skeleton
usually has a uniform distribution of yellow marrow in adults.
MRI Appearance of Normal Marrow
The MR appearance of the bone marrow depends on the pulse
sequence selection and the relative amounts of cellularity, protein,
water, and fat within the marrow. Spin-echo and fat-suppressed
sequences have been most widely used to image bone marrow. The
addition of other sequences will be influenced by the disease process
and anatomic region being evaluated.T1-weighted spin-echo sequences
allow superb differentiation between red and yellow marrow.
On T1-weighted images, hematopoietic marrow usually shows a
signal intensity equal to or slightly higher than that of muscle on both
T1- and T2- weighted sequences. In neonates, the signal intensity of
hematopoietic marrow may be slightly lower than that of muscle on
T1-weighted images, reflecting the larger percentage of cellular
9
marrow. After the neonate period, signal intensity lower than normal
muscle almost always indicates pathology. Yellow marrow is isointense
with subcutaneous marrow onT1-weighted spin-echo sequences. On
T2-weighted spin-echo sequences, the signal intensity of fatty marrow
is usually higher than that of muscle and equal to or slightly lower than
that of subcutaneous fat.
Contrast differences between normal and pathologic marrow and
between red and yellow marrow on T2-weighted images can be
accentuated by using fat-suppressed sequences, either the fat-saturation
technique or STIR images13.On these sequences, hematopoietic marrow
shows intermediate signal intensity similar to that of muscle, whereas
fatty marrow shows a signal intensity lower than that of muscle. By
comparison, most marrow pathology exhibits relatively high signal
intensity, greater than that of red and yellow marrow, on fat-suppressed
images. The use of contrast-enhanced MRI can also improve lesion
conspicuity. Normal marrow shows minimal enhancement after admini-
stration of gadolinium chelate agents. By comparison, many malignant
neoplasms exhibit an increasing signal intensity that is greater than the
increase shown by normal marrow and by benign lesions14.
10
Distribution of Normal Marrow
The ability to recognize the normal variations in bone marrow
distribution is important so that they are not interpreted as abnormal.
Bone marrow is a dynamic organ that changes composition throughout
life (Fig1)3,4,15,16. At birth, the marrow contains a predominance of
hematopoietically active cells. Shortly after birth, an orderly and
predictable conversion of hematopoietic to fatty marrow takes place,
which begins in the appendicular or peripheral skeleton and progresses
to the axial or central skeleton. Within individual long bones, marrow
conversion occurs first in the diaphysis, then in the distal metaphyses,
and finally in the proximal metaphyses. The adult pattern of marrow
distribution is reached by the middle of the third decade. At this time,
red marrow is predominantly seen in the axial skeleton (skull, spine,
sternum, flat bones) and the proximal ends of the humerus and
femurs; yellow marrow predominates in the remainder of the long bones
and the epiphyses and apophyses(Fig2) 15,22 . islands of red marrow can
also be seen in the distal ends of the femurs in marathon runners and
menstruating women.
One common exception to the normal pattern of complete
conversion is the epiphyses. The epiphyses are cartilaginous before they
ossify. Cartilaginous epiphyses and apophyses exhibit signal intensity
equal to that of muscle on T1-weighted images and equal to or slightly
11
higher than that of fat on T2-weighted images. Once ossification has
been present for 3 to 4 months, the epiphyses and apophyses exhibit
high signal intensity on both T1- and T2-weighted images, reflecting
their predominantly fatty marrow. How-ever, islands of low-signal-
intensity red marrow can be seen within the subchondral regions of the
proximal humeral epiphyses on T1-weighted images in healthy
adolescents and adults23 .
Age-related changes in marrow conversion have also been
addressed in the axial skeleton. In the first decade of life, the vertebral
marrow is predominantly hematopoietic and shows homogeneously low
signal intensity except for high signal intensity around the basivertebral
vein. With aging, the amount of hematopoietic marrow in the vertebral
bodies progressively decreases, but even in adults the vertebral bodies
contain abundant red marrow. The decline in red marrow is
accompanied by an increase in fatty marrow. In the first decade of life,
the signal intensity of the vertebral bodies is often lower than that of the
adjacent disk space. In individuals older than 10 years, the signal
intensity of the vertebral marrow is higher than that of the
adjacent disk. The conversion of red to yellow marrow in the vertebral
bodies can occur in a diffuse or focal pattern 19.
12
An age related pattern of red to yellow marrow conversion also
occurs in the pelvis. Pelvic marrow is pre dominantly hematopoietic in
the first two decades of life 17. Red to yellow conversion begins in the
acetabulum superiorly and medially. By the third decade, these areas
usually contain mainly fatty marrow.
Fig 1.Normal conversion of hematopoietic marrow into fatty marrowfrom birth to 70 years. Diagram shows percentages of hematopoieticmarrow at different anatomic sites. Conversion of red to yellow marrowoccurs earlier in appendicular than in axial skeleton
13
Fig 2.Normal distribution pattern of adult marrow. Hematopoietic mar-row (in red) resides in skull, vertebral bodies, flat bones, and proximalfemoral and humeral metaphyses. Fatty marrow (in yellow) predomi-nates in remainder of skeleton
Fig 3.BM trephine biopsy sectionshowing normal bone structure; thereare anastomosing bonytrabeculae. Paraffi n - embedded, H & E× 5.
14
Classification of bone marrow disorder:
Disorders that affect marrow production can be divided into four
categories:
1. Marrow reconversion or hyperplasia,
2. Marrow infiltration disorders,
3. Myeloid depletion disorders (hypo cellular or fatty marrow)
4. Myelofibrosis
Others like bone marrow ischemia (avascular necrosis,
medullary infarct), bone marrow edema
1. Marrow Reconversion (Myeloid Hyperplasia):
Marrow reconversion refers to the repopulating of yellow marrow by
hematopoietic cells. Fatty marrow reconverts to red marrow where there
is an increased demand for Haematopoiesis and the hematopoietic
capacity of existing red marrow stores is exceeded. Reconversion occurs
in a pattern opposite that of physiologic marrow conversion, beginning
in the vertebrae and flat bones of the pelvis and then progressing to the
long bones of the extremities and ultimately to the hands and feet. In
15
the individual long bones, marrow reconversion first occurs in the
proximal metaphyses, followed by the distal metaphyses, and the
diaphysis. Reconversion occurs in the epiphyses and apophyses only
when severe hematopoietic stress is present.
Causes of reconversion include
i) Severe chronic anaemia(such as sickle cell disease, thalassemia,
or hereditary spherocytosis),
ii) Treatment with granulocyte-macrophage colony-stimulating
factor (GMCSF) during chemotherapy,
iii) Circumstances in which an increased oxygen requirement is
present (e.g., rigorous athletics such as marathon running and
high altitudes)
2.Marrow Replacement Disorders:
Marrow can be replaced or infiltrated by number of disorders,
Including leukemia, lymphoma, multiple myeloma, and metastases.
Diseases such as leukemia, lymphoma, and multiple myeloma tend to
originate in the hematopoietic marrow. Metastases localize in the red
marrow because it has a richer blood supply than fatty marrow. In adult
patients, the common sites for metastatic disease are the
16
vertebrae (69%), pelvis (41%), proximal femoral metaphyses (25%),
and skull (14%)
3. Myeloid Depletion:
Myeloid depletion refers to the loss of normal red marrow.
Pathologically, the marrow is acellular or hypo cellular, with yellow
marrow filling the marrow space.
Causes of myeloid depletion include
i) Viral infections,
ii) Medications,
iii) Chemotherapy
iv) Radiation therapy,
But in many instances, the cause is unknown. Aplastic or
hypo plastic marrow shows diffusely high signal intensity on both
T1- and T2-weighted images and low signal on fat-suppressed
images 30,31 . The increase in fatty marrow is best appreciated in areas
that normally contain a predominance of red marrow, such as the spine
and pelvis. Radiation is a cause of focal marrow depletion. Radiation in-
duced changes have been most often described in the spine32,34 Initial
pathologic changes include edema, vascular congestion, and diminished
17
haematopoiesis. The marrow subsequently is replaced by fat and
fibrosis. These changes are usually complete by 3 months after the start
of therapy. Alterations in marrow signal intensity can be observed as
early as 2 weeks after initiation of treatment, especially on STIR images.
The early pattern is that of low signal intensity on T1-weighted images
and high signal intensity on T2-weighted and fat-suppressed sequences.
The later pattern of fatty replacement usually appears as homogeneous
high signal intensity within the radiation port on T1- weighted images.
Fatty replacement also can be noted in non radiated vertebral marrow
adjacent to the radiation port in approximately 50% of patients.
Decreased contrast enhancement of the nonirradiated bone marrow
during and after the end of radiation has been reported on dynamic MRI
and is thought to reflect the effect of radiation on the microvasculature
of marrow 35.
Most patients have some degree of hematopoietic marrow
recovery within 1 to 2years after radiation therapy. Chemotherapy also
results in initial ablation of hematopoietic cells and marrow replacement
by edema. Changes in the first few days after the administration
of chemotherapy include decreased signal intensity on T1-weighted
images and increased signal intensity on T2-weighted and
18
fat-suppressed sequences. After the initial changes subside, the marrow
may repopulate with normal elements or the cellular elements may be
replaced by fat or a combination of fat and fibrosis.
4. Myelofibrosis:
Myelofibrosis is characterized by replacement of normal marrow
cells by fibrotic tissue. It usually is the result of radiation therapy or
chemotherapy, but on occasion it can be a primary disorder. Fibrotic
marrow usually produces low signal intensity on both T1- and
T2-weighted images.
The signal intensity may be slightly higher than that of muscle on
fat-suppressed images. Differential considerations for hypo intense
signal intensity include Gaucher’s disease and hemosiderosis.
Gaucher’s disease is an autosomal recessive disease characterized by
decreased levels of the enzyme glucocerebrosidase, leading to
accumulation of glucocerebrosides within histiocytes in the monocyte-
macrophage system. Marrow disease usually follows the distribution of
reconverted marrow and begins in the spine, pelvis, and proximal
femoral metaphyses. Within the long bones, it progresses from a proxi-
mal to distal distribution. Epiphyseal marrow is rarely involved unless
19
extensive disease is present 36.Hemosiderin deposition can occur secon-
dary to the breakdown of RBCs in haemolytic anemias or as a sequela of
chronic blood transfusions 37. The magnetic susceptibility effects of
hemosiderin produce hypointense marrow on all pulse sequences. The
marrow signal intensity is usually lower than that of normal
hematopoietic marrow. Low signal intensity also can be seen in the liver
and spleen.
Marrow Ischemia:
This category of bone marrow disease encompasses both avascular
necrosis of subchondral bone and medullary bone infarcts. Bone
marrow ischemia favours fatty marrow over hematopoietic marrow.
This is most likely due to the limited vascular supply of yellow marrow
relative to red marrow.
Marrow Edema
Bone marrow edema is usually focal. There is a nonspecific increase
in water content within the bone marrow which manifests decreased
signal intensity on T1 weighed spin-echo images, and markedly
increased signal intensity on STIR images and T2weighted fast
spin-echo images with fat saturation. T2* weighted images are
20
frequently less sensitive in detecting bone marrow edema due to
obscuration of the high signal from the edema by magnetic
susceptibility “blooming“ of trabeculae. The finding of bone marrow
edema is non specific ,and can be seen as a result of trauma, infection,
ischemia, reaction to adjacent neoplasia, or it may be idiopathic. For
example, the bone marrow edema seen on MR images of the hip may be
secondary to transient or migratory osteoporosis, early osteonecrosis, or
the bone marrow edema syndrome.
MR SEQUENCES:
Pulse sequence selection determines the MR appearance of
normal bone marrow as well as the sensitivity and specificity for
evaluating bone marrow disorders. A highly effective combination of
pulse sequences for the evaluation of bone marrow pathology includes:
(1) T1 weighted spin-echo;
(2) fat-saturation T2 weighted fast spin-echo;
(3) STIR/FastSTIR
(4) opposed phase image.
21
T1 weighted spin-echo
There is superb differentiation between red and yellow bone
marrow on T1 weighted spin-echo images. On T1 weighted images the
yellow marrow is hyperintense in signal intensity as contrasted with the
relatively decreased signal intensity of red marrow. These differences in
signal intensity are a direct reflection of the differences in fat/water
content within red and yellow marrow. Specifically, increased fat
content within yellow marrow contributes to significant shortening of
the T1 relaxation time compared with red marrow. Both benign and
malignant disorders of bone marrow have long T1 values which result in
marrow signal intensity that is significantly decreased. The signal
intensity of these lesions on T1 weighted spin-echo images is usually
less than that of inter vertebral discs in the spine and less than that of
muscle in the extremities.
T2 weighted fast spin-echo and STIR
The clinical advantages of STIR are due to the following
characteristics:
(1) Additive T1 and T2 contrast; (2) marked fat suppression; (3) a
two-fold increase in the magnetization range of spin-echo sequences. As
22
a result, STIR images demonstrate extraordinarily high contrast,
conspicuousness, and sensitivity for the depiction of most types of bone
marrow pathology. The obvious drawbacks of this pulse sequence,
however, include relatively long imaging times, and allow signal-to-
noise ratio. Conventional intermediate weighted and T2 weighted spin-
echo sequences demonstrate relatively low contrast between red marrow
and yellow marrow. In addition there is decreased sensitivity and
conspicuousness for the depiction of most types of bone marrow
pathology. These problems are corrected by utilizing the very long TR
and TE times of heavily T2weighted fast spin-echo images used in
conjunction with fat saturation. The sensitivity of this sequence for
detecting bone marrow pathology is similar to that of STIR imaging.
Several practical advantages compared with STIR include:
(1)significantly decreased imaging time; (2) improved signal-to-noise
ratio. The major disadvantage of T2 weighted fast spin-echo with fat
saturation is its dependence on excellent magnetic field homogeneity for
adequate fat suppression. Optimal results with fat saturation usually
require high-field strength systems, whereas STIR images can be
obtained on low-or high field strength systems. The fast inversion
recovery techniques significantly reduce the imaging time required for
STIR-like images. The role of these techniques in the evaluation of bone
23
marrow pathology is currently evolving. Recent studies suggest an
emerging role for this pulse sequence for performing whole body bone
marrow MRI for the evaluation of patients with suspected skeletal
metastasis or multiple myeloma.
Opposed phase image
Opposed-phase GRE sequences with a long repetition time have
recently been shown to be sensitive for demonstrating red bone marrow
pathology. This type of sequence results in low signal intensity of intact
redbone marrow and high signal intensity positive contrast imaging of
pathology.
Several studies have illustrated the potential use of MR in bone
marrow imaging. MR imaging is sensitive in the detection of areas of
abnormal marrow. But most neoplastic and non-neoplastic lesions in the
bone marrow may have similar signal intensity on conventional MR im-
aging sequences.
Only few studies have illustrated the use of in phase opposed
imaging in bone marrow.
Disler et al.38-Thirty consecutive patients with 31 suspected bone
marrow lesions underwent MR imaging, including two spoiled gradient-
echo sequences identical in all parameters except TE which was chosen
24
such that fat and water were either in phase or out of phase. Relative
ratios of the abnormal bone marrow signal intensity and a control site on
the in-phase and out-of-phase images were expressed. The images were
also assessed independently by two reviewers who were unaware of the
patients identities and clinical histories. Reviewers assessed decreased
marrow signal intensity relative to control sites on the out-of-phase and
in-phase images. Pathologic confirmation was obtained in 16 patients
(17 lesions): the remainder of patients had either established diagnoses
or determination of benignity based on stability of findings at I year.
Relative ratios were compared with the Student’s t test and receiver
operating characteristic (ROC) curve analysis and the reviewers’ scores
were evaluated with ROC curve analysis. The relative signal-intensity
ratios were I .03 ± 0. 13 for the neoplastic group and 0.62 ± 0.13 for the
non-neoplastic group (p <.0001). ROC curve analysis of the signal-
intensity ratios showed z-score of 0.99. A ratio cut off value of 0.81
resulted in 95% sensitivity and 95% specificity for detection of
neoplasm. Both reviewers achieved 100% sensitivity and 94-100%
specificity for detection of neoplasms. In-phase and out-of-phase
gradient-echo MR imaging of bone marrow signal- intensity
abnormalities can help predict the likelihood of neoplastic or
non-neoplastic lesions. absent
25
One group of lesions absent from Disler et al study was
osteomyelitis, which we would expect to exhibit a range of relative
signal-intensity ratios, depending on the degree of infiltration of marrow
by inflammatory cellular elements and on whether abscess formation
occurred.
Erly WK, Oh ES, Outwater EKet al 39- Twenty-five
consecutive patients who were evaluated for suspected malignancy
(lymphoma [4 patients], breast cancer [3], multiple myeloma [2],
melanoma [2], prostate [2], and renal cell carcinoma [1] or for trauma to
the thoracic or lumbar spine were entered into this study. An 18-month
clinical follow-up was performed. Patients underwent standard MR
imaging with an additional sagittal in-phase (repetition time [TR], 90–
185; echo time [TE], 2.4 or 6.5; flip angle, 90°) and opposed-phase
gradient recalled-echo sequence (TR, 90–185, TE, 4.6–4.7, flip angle,
90°). Areas that were of abnormal signal intensity on the T1 and T2
sequences were identified on the in-phase/opposed-phase sequences. An
elliptical region of interest measurement of the signal intensity was
made on the abnormal region on the in-phase as well as on the opposed-
phase images. A computation of the signal intensity ratio (SIR) in the
abnormal marrow on the opposed-phase to signal intensity measured on
the in-phase images was made. Twenty-one patients had 49 vertebral
lesions, consisting of 20 malignant and 29 benign fractures. There was a
26
significant difference (P < 0.001, Student t test) in the mean SIR for the
benign lesions (mean, 0.58; SD, 0.02) compared with the malignant
lesions (mean, 0.98; SD, 0.095). If a SIR of 0.80 as a cut-off is chosen,
with >0.8 defined as malignant and <0.8 defined as a benign result,
in-phase/opposed-phase imaging correctly identified 19 of 20 malignant
lesions and 26 of 29 benign lesions (sensitivity 0.95; specificity, 0.89).
There is significant difference in signal intensity between benign
compression fractures and malignancy on in-phase/opposed-phase MR
imaging. Conversely, based on the current data, it is clear that some
benign fractures do not contain sufficient fat to suppress on the opposed-
phase sequences. The evolution of the signal intensity changes in benign
compression fractures over time with this technique is not known. It
may be that the number of false-positives for malignancy of this
technique may be reduced when used within a specified time period
after the occurrence of a fracture.
27
MATERIAL AND METHODS:
Study design: prospective study
Study period: May 2008 to May2010
Subjects:
The study population consisted of 38 consecutive patients with
suspected bone marrow lesions between the years May 2008 to May
2010 included in the study. The study group consisted of 22 male and 16
female patients, between the age of 11 to 70 years (with a mean age of
40 years). For 26 patients pathological confirmations obtained.
Subjects are followed up for a period of 1 year.
The study was approved by the ethical committee and lasted for
24 months.
Inclusion criteria:
Patients with T1 hypo intense ,T2 hyper intense lesion in the bone
marrow MRI
Fracture less than 10 days only included
28
Exclusion criteria
Patients with post surgical changes were excluded from the study.
Fracture more than 10 days
Patients with Pacemaker & Metallic Implants.
Claustrophobic patients.
Patient preparation
No specific preparation
Methods:
MR Imaging protocol:
All patients were studied with 1.5-T MR imaging units (Seimens
machine).
Various standard imaging sequences were routinely used, including
1. T1(TR 400-600, TE 10-20)
2. T2(TR3000- 4000, TE 80- 120)
3. STIR (TR 4000-6000, TE60-100, IT 100-150msec)
29
Field of view, matrix size, slice thickness and interslice gap were
tailored to the specific site under study. Choice of coils was also
dependent on the specific anatomic site under study. In addition to the
routine sequences all the enrolled patients underwent imaging with two
fast multiplanar spoiled gradient-echo sequences.
1.Inphase(TR 100 -120 ,TE4.6 -4.8 msec)
2.Opposed phase(TR 100-120, TE 2.4 -2.6 or 7.2)
Which was selected to image lipid and water spins in phase(4.6 to
4.8 msec) or opposed phase (2.4-2.6 msec or 7.2msec). Ideally the TE
on the opposed-phase images would be 2. 1 msec (with fat and water
spins directly opposed): however TE ranged between 2.4 and 2.9msec in
18 patients because of inherent gradient limitations imposed by the se-
lection of the other imaging parameters. Also, because of gradient
limitations, an opposed phase TE of 2.4-2.9 msec could not be selected
in 12 patients and thus an opposed phase TE of 7.2 msec was chosen for
these patients. Although a TE as short as possible should be chosen to
minimize signal-intensity differences due to T2*effects, these effects
would likely be small with the short TEs used in the study. TR ranged
from 100 to120 msec. Other imaging parameters included 256 x 192
matrix and a 32-kHz bandwidth.
30
IMAGE ANALYSIS:
Circular regions of interest as large as possible to include only the
abnormal marrow signal intensity under study were selected, identical in
location on the in-phase and opposed-phase images and the signal
intensity values were recorded. In addition to the foci of abnormal bone
marrow signal intensity. Signal intensity in normal-appearing
hematopoietic bone marrow (if present) and a skeletal muscle. bladder
cavity or saline-phantom control site were recorded. Control sites were
chosen as homogeneous tissues containing little or no mixed water and
fat, which should not experience loss of signal on the opposed phase
images due to opposed lipid and water spins. Signal-intensity ratios
were expressed for the in-phase images and the opposed-phase images
as signal-intensity ratio= normal or abnormal bone marrow signal-
intensity /control signal intensity (muscle. urine [in bladder, or saline
phantom).
Relative signal-intensity ratios were then expressed for
comparison of the opposed-phase ratios with the in-phase ratios as
Signal-intensity ratio of opposed phase imageRelative signal-intensity ratio =
Signal-intensity ratio of in phase image
31
to determine if a change occurred in the signal intensity of the lesion
with opposed phase imaging. A decrease in signal intensity was
considered indicative of both lipid and water protons within the lesion.
The opposed phase and in-phase images for each patient were
then reviewed independently by two radiologists. who were experienced
in musculoskeletal MR imaging and were unaware of patient identity
and clinical information, to visually determine if the signal intensity of
the lesion relative to the control site decreased on the opposed phase
images compared with the in phase images. Each radiologist graded
each patient’s images on a five-point scale of confidence for
identification of decreased signal intensity in the lesion as follows:
grade 1. Definitely no decrease in signal intensity in the lesion relative
to the control site on opposed phase images:
grade 2, probably no decrease in signal intensity in the lesion relative to
the control site on opposed phase images;
grade3, indeterminate;
grade 4, probably a decrease in signal intensity in the lesion relative to
the control site on opposed phase images;
32
grade 5, definitely a decrease in signal intensity in the lesion relative to
the control site on out-of-phase images. The two radiologists then
reviewed the images together and gave each patient a consensus grade.
26 patients (26 lesions) underwent biopsy or definitive surgery
subsequent to MR imaging.and their lesions were categorized as neo-
plastic or nonneoplastic.
Of the remaining 12 were designated nonneoplastic on the basis
of resolution of symptoms , imaging findings after at least 1 year , the
basis of MR imaging findings diagnostic of avascular necrosis of bone
and stability of findings at 1 year.
33
OBSERVATION &RESULTS:
Relative Signal intensity ratio (Relative SIR) calculated for all 38
patients
Fig4 distribution of Relative SIR of neoplastic lesions
Fig 5. distribution of Relative SIR of non neoplastic lesions
34
Fig 6.Data comparison graph shows mean difference between thebenign and malignant lesion
Fig 7. Comparison of relative SIR of malignant and benign lesions
35
STATISTICAL ANALYSIS:
Statistical analysis were performed with a statistical software
system (SPSS Version 17.0 [SPSS] for Windows [Microsoft]
Results were analyzed by following statistical methods
1. Students T test
2. Chi-square test
3. ROC analysis
T-Test:
Group Statistics
Bone marrow N Mean Std deviationStd. Error
Mean
Relative SIR Malignant 19 1.081 0.1257 0.0288
Benign 19 0.615 0.1546 0.0355
P value
< 0.001**
P value0.001** means test is <1% level significant
36
Independent Samples Test:
t-test for Equality of Means
t df Sig. (2-tailed)
MeanDiffer-ence
Std. Er-ror Dif-ference
95% ConfidenceInterval of the
DifferenceLower Upper
RelativeSIR 10.202 36 .000 .466 .0457 .3736 .5590
10.202 34.563 .000 .466 .0457 .3735 .5591
Crosstabs
Bonemarrow Disorders * Relative SIR Crosstabulation
Relative SIR TotalPositive Negative
Count 19 0 19% within Bone-marrow Disorders 100% 0% 100.0%Malignant
% within RelativeSIR 90.5% 0% 50.0%
Count 2 17 19
% within Bone-marrow Disorders 10.5% 89.5% 100.0%
Bonemarrow
Disorders
Benign
% within RelativeSIR 9.5% 100% 50.0%
Total Count21 17 38
% within Bone-marrow Disorders 55.3% 44.7% 100.0%
% within RelativeSIR 100.0% 100.0% 100.0%
37
Chi-Square Tests:
Value dfAsymp.Sig. (2-sided)
ExactSig. (2-sided)
ExactSig. (1-sided)
Pearson Chi-Square 30.762(b) 1 .000Continuity Correc-tion(a) 27.249 1 .000
Likelihood Ratio 39.471 1 .000Fisher's Exact Test .000 .000Linear-by-LinearAssociation 29.952 1 .000
N of Valid ases 38
a Computed only for a 2x2 table b 0 cells (.0%) have expected count
less than 5. The minimum expected count is 8.50.
ROC Curve
Case Processing Summary
Bone marrow Disorders Valid N (list wise)
Positive(a) 19
Negative 19
Larger values of the test result variable(s) indicate stronger evidence for
a positive actual state. a The positive actual state is malignant
38
1 - Specificity1.00.80.60.40.20.0
Sensiti
vity
1.0
0.8
0.6
0.4
0.2
0.0
ROC Curve
Area Under the Curve
Test Result Variable(s): Relative SIR
Area Std. Error(a) AsymptoticSig.(b)
Asymptotic
95% Confidence Interval0.986 0.013 0.000 0.960 1.012
a Under the nonparametric assumption
b Null hypothesis: true area = 0.5
39
Coordinates of the Curve
Test Result Variable(s): Relative SIR
Positive if GreaterThan or Equal to (a) Sensitivity 1 - Specificity
-.620 1.000 1.000.400 1.000 .947.450 1.000 .895.490 1.000 .842.505 1.000 .737.515 1.000 .684.530 1.000 .632.550 1.000 .579.580 1.000 .526.610 1.000 .421.645 1.000 .368.675 1.000 .316.690 1.000 .263.730 1.000 .211.770 1.000 .158.820 1.000 .105.870 .947 .105.890 .895 .105.910 .895 .053.940 .842 .053.970 .842 .000.990 .737 .0001.010 .684 .0001.040 .632 .0001.070 .579 .0001.090 .526 .0001.150 .316 .0001.230 .105 .0001.280 .053 .0002.300 .000 .000
a The smallest cut off value is the minimum observed test value minus
1, and the largest cut off value is the maximum observed test value
plus1.
40
In ROC curve If 0.82 as taken as cut off, test shows
100%sensitivity,89.5%specificity. .
Visual interpretation also obtained same results
If 0.82 as taken as cut off value
MALIGNANT BENINGN
POSITIVE 19 2
NEGATIVE 0 17
19 19
Sensitivity 100%
Specificity 89.5%
positive predictive value 90%
negative predictive value 100%
Statistical analysis also shows the test highly significant with the
P Value <0.0001
41
84%
86%
88%
90%
92%
94%
96%
98%
100%
sensitvity specificity PPV NPV
Fig 8 Comparison of sensitivity, specificity, PPV and NPV
Fig 9. 1.5 Tesla seimens machine used for this study
Fig 10.Method of signal intensity ratio calculation in inphase image
Fig 11.method of signal intensity ratio calculation in opposed phase image
NET RF SIGNAL
WATER
FAT
IN PHASE TE 4. 6msec
Fig12.illustration of the physical principles of in-phase imaging.At echo time (TE) of 4.6 ms, both the fat and water protons are in phase, and
signal intensity is received from voxels containing both tissue types.
WATER
FAT
OPPOSED PHASE TE 2.4 sec
RF SIGNAL
Fig 13 illustration of the physical principles of opposed phase imaging At TEof 2.4 ms, the protons on water and fat molecules are 180°
opposed, and the signal intensity from one cancels the signal intensity from theother. Voxels that contain both tissue types have a reduction in signal intensity.
WATER
FAT
OPPOSED PHASE TE 2.4 sec
RF SIGNAL
Fig 14 illustration physical principal of opposed phase imaging inneoplastic Lesion. Neoplastic lesion infiltrate the fatty marrow, so fat an water
not is not equal, it will cause no signal suppression in opposed phase image
CASE 1MULTIPLE MYELOMA
Fig15A Inphase image
Fig 15B Opposed phase imageNeoplastic lesion (multiple myeloma) of bone marrow shows no signal
Suppression (hyperintense) in opposed phase image
CASE 2APLASTIC ANEMIA
Fig 16A
Fig 16B
Fig16 A inphase image FIG 16B opposed phase imageon neoplastic lesion(marrow reconversion-red marrow) of bone marrow shows
complete signal loss in opposed phase image
CASE 3
Carcinoma cervix with metastasis
Fig 17.Neoplastic lesion (metastasis) of bone marrow shows no signalSuppression (hyperintense) in opposed phaseimage. but Post radiotheraphy
changes in L5 and sacrum also hyper intense in opposed phase image
Case 4Metastaic adenocarcinoma
Fig 18.Neoplastic lesion (metastasis) of bone marrow shows no signalSuppression (hyper intense) in opposed phase image
Case 5TB spondylitis
Fig 19. Opposed phase image of TB spondylitis . It shows no signalsuppression in opposed phase image because infection also causes
infiltration of fatty marrow
CASE 6
NHL (Non Hodgkins Lymphoma)
Fig 20.Neoplastic lesion (NHL) of bone marrow shows no signal Suppression
(hyper intense) in opposed phase image
42
DISCUSSION:
Our results showed that in-phase and opposed of- phase spoiled
gradient-echo MR Imaging was helpful in predicting the likelihood of
neoplastic or non neoplastic signal abnormality in bone marrow. Visual
assessment and expression of relative signal-intensity ratios were found
to be of similar accuracy. we generated ROC curves that revealed 95%
sensitivity and specificity for detection of neoplasm at a relative signal-
intensity ratio cut off value of 0.82. No nonneoplastic lesion had a value
greater than 0.96. and no neoplastic lesion had a value less than
0.86.Thus. for our patient group a cut off value between 0.82 would re-
sult in 100% sensitivity and 89.5% specificity for detection of neoplasm.
In-phase/opposed-phase imaging to assess for the presence of fat
and water in a voxel of tissue has been used extensively in imaging of
the liver and adrenal glands. The technique takes advantage of different
precession frequencies of water and fat protons due to the differences in
their molecular environment. Because they precess at slightly different
frequencies, at 1.5T, water and fat protons are in phase with one
another at a TE of 4.6 ms, and 180° opposed at a TE of 2.4 msec. This
phenomenon is not usually evident on spin-echo sequences. Without a
refocusing pulse, when there are both fat and water protons in a given
43
voxel, there will be some signal intensity loss on images that are
obtained when the protons are in their opposed phase (TE _ 2.4 ms) .
More signal intensity suppression occurs when the volume of fat and
water is roughly equal. This technique is useful in identifying presence
of fat coexistent with water in marrow lesions, thus predicting the
likelihood of neoplasm in patients with marrow signal-intensity
abnormalities. This likelihood is possible because most neoplastic
lesions of bone marrow exist as solid masses with advancing fronts that
completely destroy and replace all lipid and hematopoietic elements.
whereas most nonneoplastic lesions (with the exception of tumour like
lesions of bone such as bone cysts and fibrous dysplasia) do not exist as
solid masses but rather as infiltrative hemorrhagic or inflammatory
elements that comingle with, rather than replace, fat Signal that
decreases in intensity on opposed phase compared with in-phase images
indicates that fat and water are present in an area of marrow signal-
intensity abnormality making neoplasm less likely. On the other hand.
Signal intensity that does not decrease on opposed phase images
indicates that fat and water are not coexistent. Making neoplasm more
likely. Marrow dominated by fat also will not decrease in signal
intensity on opposed phase images: however, the presence of fatty
marrow is readily recognized by its high signal intensity on
44
conventional Tl weighted images . In this study. Tissues with significant
signal contributions from both lipid and water (such as the cases of
edema within avascular necrosis and fractures and normal and
hyperplastic hematopoietic marrow) had cancellation of signal on the
opposed phase images. resulting in decreased signal intensity compared
with the in-phase images. On the other hand tissue dominated by water
spins (such as the cases of metastases) showed little or no decrease in
relative marrow signal intensity on the opposed phase images compared
with the in-phase images.
45
Fig 20 Illustration of the physical principles of in-phase/opposed-phase
A) Inphase B)Opposed phase
46
ADVANTAGES OF OPPOSED PHASE IMAGING:
i). A major advantage is that the technique can be performed
rapidly. Imaging with in-phase and opposed phase imaging se-
quences adds at most 4-5 minutes to total imaging time.
ii). In addition. the techniques widely available: in-phase and
opposed phase MR imaging is standard on most systems. .
iii). Because both quantitative and visual interpretation appear equally
accurate for assessment of focal marrow abnormalities either can
be used. Thus allowing for rapid interpretation from visual
assessment.
iv) The potential clinical use of this technique for avoiding
unnecessary biopsy
.v) It is also guiding tool for the biopsy
47
LIMITATIONS OF THE STUDY:
I) Two TB spondylitis lesion shows high relative signal intensity
ratio (>0.8) signal intensity in TB spondylitis depending on the
degree of infiltration of fatty marrow by inflammatory cellular
elements and on whether abscess formation occurred.
ii) Some patients did not have direct pathologic correlation.
iii) Post radiotherapy shows lack of signal suppression in opposed
phase image
iv) Only 38 patients were included in the study. This patient
population may be small because a large variety of lesions can
affect bone marrow. This results should be considered preliminary
and in need of further evaluation. Future studies involving large
patient groups may be helpful to determine the usefulness of this
technique for specific marrow disorders.
48
CONCLUSION:
In-phase/opposed-phase imaging helpful in differentiating
Neoplastic lesions from non neoplatic lesions of bone marrow.
Furthermore, it may be an early indicator of response to treatment after
radiation therapy to the spine .In-phase and opposed phase imaging
sequences performed rapidly and just it adds only 4-5 minutes to total
imaging time. In phase Opposed phase imaging has ability to
demonstrate small amounts fat and fat- water mixture is the strongest
advantage of this technique both quantitative and visual interpretation
appear equally accurate for assessment of focal marrow
abnormalities. either can be used. Thus allowing for rapid interpretation
from visual assessment. TB spondylitis(non neoplastic lesion) included
in this study shows high relative SIR . signal intensity in TB spondylitis
depending on the degree of infiltration of fatty marrow by inflammatory
cellular elements. So use of in phase opposed phase imaging in infection
should be evaluated more.
49
In-phase/opposed-phase imaging is fast , most sensitive.Easly
interpretable and useful sequence, in differentiating Neoplastic lesions
from non neoplatic lesions of bone marrow.
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INPHASE OPPOSED IMAGING OF BONE MARROW
DIFFERENTIATING NEOPLASTIC LESIONS FROM
NON NEOPLASTIC LESION
PROFORMA
NAME: AGE/ SEX : STUDY NO:
ADDRESS
PHONE NO
CLINICAL HISTORY:
PAST HISTORY:
RISK FACTORS:
Inphase image Opposed phase image Diagnosis Biopsy
SIR oflesion
SIR ofcontrolsite
SIR ofinphaseimage
SIR oflesion
SIR ofcontrol
site
SIR ofopposed
phaseimage
RelativeSIR
ABBERVIATIONS:
ALL - Acute Lympocytic Leukemia
CLL - Chronic Lymphocytic Leukemia
MRI - Magnetic Resonance Imaging
NHL - Non Hodgkins Lympoma
GRE - Gradient Recalled Echo
ROC – Receiver Operating Characteristic Curve
SIR - Signal Intensity Ratio
STIR - Short Time of Inversion Recovery
TR - Time of Repetition
TE - Time of Echo
SNO NAME AGE SEXBONE MARROW
DISORDERS
RELA-
TIVE
SIR
23 mari 42 M TB spondylitis 0.90
24 Abdul reh-
man
43 M Hyperplastic red marrow 0.42
25 arunkumar 18 M Hemosiderotic marrow 0.38
26 Peula 36 F Avascular necrosis 0.56
27 kamala 52 F Traumatic fracture 0.60
28 selvi 47 F TB spondylitis 0.96
29 muthukumar 17 M Aplastic anemia 0.48
30 kavitha 25 F Hyperplastic red marrow 0.50
31 ponnusamy 62 M Traumatic fracture 0.67
32 gajendran 41 M TB spondylitis 0.78
33 janaki 37 F Bone infarct 0.51
34 thiyagarajan 22 M Hyperplatic red marrow 0.52
35 periyasamy 64 M Traumatic fracture 0.62
36 priya 32 F Avascular necrosis 0.54
37 arumugam 67 M Traumatic fracture 0.68
38 rajendran 23 M Aplstic anemia 0.50
MASTER CHART
SNO NAME AGE SEXBONE MARROW
DISORDERS
RELA-
TIVE
SIR
1 shanmugam 65 M Multiple myeloma 1.2
2 murugan 62 M Multiple myeloma 1.1
3 palani 45 M NHL 1.26
4 swetha 14 F ALL 1.06
5 kumari 56 F metastasis 1.08
6 rajamani 49 F metastasis 0.92
7 raja 55 M CLL 1.2
8 kandasamy 58 M Metastasis 1.1
9 anand 13 M ALL 1.02
10 rajammal 45 F Metastasis 0.98
11 kala 34 F NHL 1.1
12 krishnan 15 M ALL 1
13 prabhu 11 F ALL 1.2
14 jegathammal 68 F Metastasis 0.98
15 kannan 42 M NHL 1.1
16 ramasamy 64 M Multiple myeloma 0.86
17 saroja 51 F metastasis 0.88
18 kalaiselvi 57 M Multiple myeloma 1.2
19 ramayee 65 F Metastasis 1.3
20 pandian 24 M Traumatic fracture 0.76
21 chellammal 34 F Bone infarct 0.60
22 kandhan 46 F Traumatic fracture 0.70